African catfish is a freshwater species with a high ability to resist brackish water conditions, but heat stress may impair the health status of fish. Thus, the impact of varying levels of water salinity (0, 4, 8, and 12 ppt) was investigated on the growth performance, survival rate, and blood biochemistry of African catfish (average weight: 180.58 ± 2.8 g and average length: 38 ± 1.2 cm) for 4 weeks; then, fish were stressed with high temperature (32 °C) for 72 h. The growth performance and survival rate were markedly higher in fish reared in 0, 4, and 8 ppt than fish in 12 ppt (p < 0.05). Before heat stress, the superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) activities, and malondialdehyde (MDA) levels were markedly increased in fish stressed with 12-ppt salinity (p < 0.05). After heat stress, all groups showed a marked increased SOD, CAT, GSH, and MDA levels than fish before heat stress in the same manner (p < 0.05). Furthermore, fish in the 12 ppt group showed severe intestinal, gill, and liver histological features. The levels of blood glucose and cortisol were markedly increased in fish exposed with 8 and 12 ppt than 0 ppt gradually either before or after heat stress (p < 0.05). The highest values of ALT, AST, urea, creatinine, and the lowest total protein, albumin, and globulin were observed in fish reared in 12 ppt. Significant salinity and heat stress interactions were seen on the ALT, AST, urea, creatinine, total protein, albumin, and globulin values (p < 0.05). The integrated multi-biomarker response (IBR) results showed marked differences among the groups and increased gradually before and after heat stress, with the highest IBR in 12 ppt. In conclusion, growing African catfish in high salinity (12 ppt) hampered the growth performance and health status while the heat stress improved the antioxidative status vis-a-vis increased lipid peroxidation along with higher stress-related markers in expressed both blood and tissue.